Abstract The primary goal of the proposed supplement is to determine the mechanism by which dietary supplementation with a vitamin E derivative protects against UVB-induced skin cancer, which is within the scope of the parent grant. The incidence of skin cancer, the most common cancer in the US, continues to rise at an alarming rate. One major risk factor is UVB radiation in sunlight, causing DNA damage and subsequent tumorigenic mutations. These UVB-induced DNA damage products across the genome are repaired by the global genome NER (GG-NER) machinery. Functional GG-NER is essential for preventing mutations and skin tumorigenesis. One of the potential effective strategies for preventing skin cancer is enhancing GG-NER through dietary supplementation with a vitamin E derivative. However, its mechanism of action remains poorly understood. Recently, we discovered a novel role for vitamin E derivative in enhancing GG-NER. Guided by our preliminary data, we hypothesize that this dietary supplement enhances GG-NER and thus inhibits UVB- induced skin cancer. Our hypothesis will be tested in two Specific Aims. Aim 1 will determine the mechanism by which the vitamin E derivative regulates GG-NER. Aim 2 will determine the mechanism by which the vitamin E derivative affects UVB-induced skin tumorigenesis in mice. Successful completion of our proposed project will vastly expand our knowledge of the mechanism of action of the vitamin E derivative in GG-NER and skin cancer, and may provide new opportunities for developing better strategies to prevent and treat skin cancer using dietary supplement vitamin E derivative. Since GG-NER is critical for tumor suppression in the skin, lungs, and brain 18, our work here in GG-NER regulation by the vitamin E derivative may not only be significant for skin cancer, but may also be applicable to other tumor types as well.